The compound of formula 1 below, the chemical name of which is 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone, is commonly known as drospirenone, also abbreviated as DRSP (abbreviation used in the remainder of the text):

Drospirenone is a synthetic steroid with progestogenic, antimineralocorticoid and antiandrogenic activity; thanks to these characteristics, drospirenone has been used for some time in the preparation of pharmaceutical compositions with contraceptive action for oral administration.
Many processes for the preparation of drospirenone are known in literature.
European patent EP 75189 B1 describes a process which, through various steps commencing from 3β,7α,15α-trihydroxy-5-androsten-17-one, reaches the intermediate 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol (also simply referred to as “triol” in the remainder of the text), from which the end product drospirenone is obtained by hot oxidation with the pyridine/water/chromium trioxide mixture (Collins reagent). The latter step constitutes the main disadvantage of the process: indeed, like all Cr(VI) compounds, chromium trioxide is a known carcinogen, the use of which is subject to legislative restrictions such that the precautions required during the use and disposal of these products make them virtually unusable. Moreover, the formation of drospirenone in the presence of chromium trioxide generates a series of impurities that reduce the reaction yield, as highlighted in patent EP 918791 B1.
In patent EP 918791 B1 it is disclosed a process that avoids the use of the Collins reagent. In this process, it is employed an oxidant system comprising an oxidizing agent such as sodium bromate and a ruthenium salt as oxidation catalyst; the product of oxidation of the triol is the compound 6β,7β;15β,16β-dimethylene-5β-hydroxy-3-oxo-17α-androstane-21,17-carbolactone, that is generally known in the field with the abbreviation 5β-OH-DRSP (abbreviation that will be used in the following description); this compound is then converted into DRSP by elimination of a water molecule between the positions 4 and 5 of the steroidal skeleton, by means of para-toluenesulfonic acid. This process too envisages the purification of drospirenone by chromatography as in EP 75189 B1. The purity of the raw drospirenone obtained by the method described in EP 918791 B1 is of 93%, a value that is far from acceptable for a pharmaceutical product. The method of EP 918791 B1 thus requires purification by means of chromatography of the crude product downstream the production process. The industrial-scale purification, by means of chromatography, of a product having a market of thousands of kg/year, is however a very significant commitment: a dedicated plant with the use of tons of silica gel, which must then be disposed of and thousands of cubic meters of solvent are required, with a huge economic commitment for the set-up and management logistics of said plant.
The above problem is overcome by the process described in patent EP 1828222 B1, in the name of the Applicant. According to the process of this patent, the crude drospirenone is obtained by the intermediate 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol, using an hypochlorite of an alkali or alkaline-earth metal (for example calcium hypochlorite) in the presence, as catalyst, of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (known as TEMPO in the field) or derivatives thereof; at the end of this reaction, a mixture of compounds is obtained, containing 5β-OH-DRSP as the main component. An acid (for example para-toluenesulfonic acid) is added to this mixture as dehydrating agent; the drospirenone obtained by this preparation route is brought to pharmaceutical grade by crystallization.
The process of EP 1828222 B1 already resolves many of the problems of the known prior art, but still requires the use of an acid, in particular para-toluenesulfonic acid, in the final phase of synthesis. It is known, from Tetrahedron Letters 27(45), 5463-5466, 1986 for example, that drospirenone is unstable to acids: the lactone ring in position 17,21 and the three-membered ring in position 6,7 are not stable in the presence of acids, reacting to give impurities that must therefore be eliminated; this complicates the overall production process of drospirenone and reduces the yields thereof.
Finally, in patent EP 1571153 B1 is disclosed a further possible method for the production of DRSP. Example 11 of this patent describes a process in which: the two carbolactols corresponding to 5β-OH-DRSP, dissolved in methylene chloride, are added to a 5% (by weight) aqueous solution of sodium bicarbonate; calcium hypochlorite, in the presence of TEMPO as catalyst, is added to the biphasic mixture containing the carbolactols; pyridine is then added, and methylene chloride is distilled at room pressure; at the end of the distillation, the reaction mixture is kept hot (that is, at the temperature of methylene chloride distillation), the solvent is distilled under reduced pressure, and the crude reaction product is first chromatographed over silica gel and finally crystallized. Also this procedure suffers from some drawbacks. In first place, it still requires, as most of the previous methods, a final step of chromatography for the isolation of the desired product; chromatography, as discussed below, is undesired in an industrial process, because it prolongs the time of production and entails the use and disposal of huge amounts of solvents and silica. Besides, in the method described in this example, the maximum temperature reached is about 40° C., namely, boiling point of methylene chloride, reached during its distillation at room pressure; this temperature cannot be overcome in this procedure, because at higher temperatures sodium bicarbonate, still present in the mixture, starts to transform into sodium carbonate, with an increase in the pH of the mixture; the higher pH caused by sodium carbonate is capable to open the lactone ring of 5β-OH-DRSP, leading to by-products and in the end to a lower yield in desired product. The relatively low temperatures taught in this example of EP 1571153 B1, however, do not afford satisfactory yields in drospirenone. The yield of drospirenone, calculated starting from 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol (combined yield of examples 7, production of the carbolactols, and 11, oxidation of the carbolactols) is 62%.
It is therefore an object of the present invention to provide an improved process for the production of drospirenone.
In particular, object of the present invention is to provide a process that avoids the need to use toxic or carcinogenic metals in the oxidation reaction of 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol as well as the need to use acids in the dehydration of 5β-OH-DRSP that forms the drospirenone, thus allowing an increase in the yield of the end product.